Migraine is a common, debilitating disorder that affects approximately 15% of the adult population. There are two major types of migraines, migraine without aura, which occurs in 85% of migraineurs, and migraine with aura. Other symptoms associated with migraines include nausea, vomiting, gastrokinetic changes and hypotension.
Current treatments for migraine generally involve two classes of compounds. The first, the ergot alkaloids and related compounds such as ergotamine tartrate, ergonovine maleate, and ergoloid mesylates (e.g., dihydroergocomine, dihydroergocristine, dihydroergocryptine, and dihydroergotamine mesylate (DHE 45)), are thought to act as alpha adrenergic blocking agents with direct stimulating effects on the smooth muscle of peripheral and cranial blood vessels and to produce depression of centralvasomotor centers. The second class of compounds, typified by sumatriptan succinate (distributed under the name IMITREX™ by Glaxo Wellcome, and described in U.S. Pat. No. 4,816,470) are thought to act as serotonin agonists specific for the 5-HT1 receptor subtype. They have some activity as serotonin agonists, though not with the specificity of sumatriptan.
All of these compounds have serious adverse effects and require supervised administration at efficacious doses. All are administered as injections, the ergot alkaloids as an intramuscular injection, and sumatriptan as a subcutaneous injection. Intravenous injection of either may result in coronary vasospasm, and all are contraindicated for patients suffering from uncontrolled hypertension due to these vasoconstrictive properties. Patients taking either type of compound frequently complain of nausea, chest tightness and other adverse effects; unwanted side effects of sumatriptan include coronary vasospasm, hypertension and angina. Recent evidence suggests that the observed sumatriptan-mediated contraction of coronary arteries may be due to the stimulation of the 5-HT1B (formerly 5-HT1Dbeta.) subtype of the 5-HT receptors (Kaumann, A. J. Circulation, 1994, 90:1141-1153).
Furthermore, it has been reported that of the 50 to 70% of patients who experience migraine symptom relief within two hours after receiving conventional antimigraine agents, 30-50% experience migraine symptoms again within the next 24 hours. These subsequent headaches are typically termed “rebound,” “relapse,” “recurrent” or “secondary” headaches.
A variety of analgesics have also been administered to migraine patients. For example, K. M. A. Welch (New Eng. J. Med. 329:1476-1483 (1993)) sets forth the following dosages of analgesics as being useful: aspirin, 500-650 mg; acetaminophen, 500 mg; naproxen sodium, 750-825 mg; tolfenamic acid, 200-400 mg; and ibuprofen, 200 mg. However, these agents are rarely effective in providing complete relief of symptoms and, after initial remission, migraine symptoms often return. The problems that occur with migraine headaches may also be present in other types of headache as well. In all cases, an ideal therapy would reduce or eliminate the symptoms associated with the initial attack and minimize the frequency of later recurrences.
Given the incidence of migraine in the population and the potential side effect liability of current methods of treating migraine, there remains a need for other methods and therapeutic agents for treatment of migraine.
Other types of primary headache disorders include tension headache, cluster headache and miscellaneous-type headache (The International Headache Society, Classification and Diagnostic Criteria for Headache Disorders, Cranial Neuralgias and Facial Pain). Existing therapies for headache disorders include, for example, non-steroidal anti-inflammatory drugs, steroids, narcotics, beta-blockers, antidepressants, and anxiolytics. However, existing therapies fare not truly effective, or they are associated with undesirable side effects, thus there continues to be a need for therapeutic agents for treatment of other headache disorders, such as tension headache and cluster headache.